This application claims priority of Japanese International Application No. PCT/JP01/06836 filed Aug. 9, 2001 which claims the priority of Japanese International Application Nos. 2000-243596 filed Aug. 11, 2000 and 2000-402893 filed Dec. 28, 2000, the complete disclosures of which are hereby incorporated by reference.
The present invention relates to an activator of peroxisome proliferator activated receptor xcex4.
The peroxisome is a small organ present in cells of animals and plants, and its matrix contains various enzymes such as catalase. The peroxisome proliferator is a substance inducing proliferation of the peroxisome. Various compounds such as fibrates, herbicides, and phthalic acid plasticizers are known to be able to induce proliferation of peroxisome.
Isseman, et al. have identified a nuclear receptor which is activated by the peroxisome proliferator and given a name of peroxisome proliferator activated receptor (PPAR).xe2x80x94Nature, 347, p645-650, 1990.
As PPAR, three subtypes such as PPARxcex1, PPARxcex3 and PPARxcex4 have been identified until now.xe2x80x94Proc. Natl. Acad. Sci. USA, 91, p7335-7359, 1994.
The above-mentioned fibrates are a class of TG (triglyceride) lowering drugs that mediate their clinical effects through activation. Further, thiazolidine compounds (Troglitazone, Rosiglitazone, Pioglitazone) useful in the treatment of diabetes are also known as ligands of PPARxcex3.
As a pharmaceutical having PPARxcex4 activating effect, there are known GW-2433 (Glaxo Wellcome), L-165041 (Merck), and YM-16638 (Yamanouchi Pharmaceutical each having the following formula: 
WO 92/10468 describes that GW-2433 can be employable for prevention and treatment of atherosclerosis.
WO 97/28115 describes that L-165041 can be employable for treatment of diabetes and suppression of obesity.
WO 99/04815 describes that YM-1663B shows effects for reducing serum cholesterol and reducing LDL cholesterol.
Recently, JBC, 272(6), p3406-3410, 1997 and Cell, 99, p335-345, 1999 describe proposal for application of PPAR xcex4 ligand as an anti-cancer agent and an anti-inflammatory agent.
European Patent 558 062 describes the following compound A which has a structure similar to that of the general formula (II) [mentioned below] representing an oxazole derivative of the invention: 
J. Immunol. Methods, 207(1), 23-31, 1997 describes a compound B having the following formula: 
All of the oxazole derivatives identified by the compound A, compound B and the general formula (II) of the invention may be described as compounds of phenoxyacetic acid type. However, there are clear structural difference between the compounds A, B and the compound of the invention, that is, the compounds A, B have no substituents at the xcex1-site, while the compound of the invention is a compound of xcex1,xcex1-dialkylphenoxy type.
In addition, while the above-mentioned EP 558 062 teaches that the compound A is of value for treatment of hyperthrombinemia and as blood pressure depressant, no mention is given with respect to an effect as PPARxcex4 ligand. Further, while the J. Immunol. Methods teaches the use of the compound B as blood pressure depressant, there is no concrete description to teach that the compound is effective as PPARxcex4 ligand.
Recently, WO 01/40207 describes a substituted oxa(thia)zole derivative showing an agonist action for PPAR xcex1, and WO 01/16120 describes an oxa(thia)zole derivative substituted with a biaryl group which is employable as a PPAR controlling agent.
In comparison with the compounds of the invention, the compound of WO 01/40207 has C(xe2x95x90O)NH as X1 and a bond as X2, and the compound of WO 01/16120 has a bond as X1 and O, X or the like as X2. Accordingly, the structural difference is clear.
The present invention provides a compound having the below-mentioned general formula (I), an oxazole derivative having the below-mentioned general formula (II), and a thiazole derivative having the below-mentioned general formula (III), all of which has an action as activator of peroxisome proliferator activated receptor xcex4.
The invention resides in a compound having the following general formula (I) or a salt thereof: 
[wherein each of R1 and R2 independently is a hydrogen atom, an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and a halogen atom substituent, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atom and a 3-7 membered substituent, an arylalkyl group that has a C6-10 aryl portion and C1-4 alkyl portion and optionally has a substituent, or an aryl or heterocyclic group which optionally has a substituent; A is O, S, or NR5 in which R5 is H or C1-8 alkyl; each of X1 and X2 independently is a bond (free valency), O, S (O)p in which p is an integer of 0 to 2, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94OR6) in which R6 is H or C1-8 alkyl; C(xe2x95x90O)NH, NHC(xe2x95x90O), SO2NH, NHSO2, CH(OR7) in which R7 is H or C1-8 alkyl, CHxe2x95x90CH, or Cxe2x89xa1C; Y is an alkylene chain having 1-8 carbon atoms and optionally a substituent; Z is O or S; each of R3 and R4 independently is an alkyl group having 1-8 carbon atoms and optionally a substituent; and R8 is a hydrogen atom or an alkyl group having 1-8 carbon atoms; provided that X2 is neither O nor S(O)p when X1 is a bond, while X2 is not a bond when X1 is C(xe2x95x90O)NH].
Further, the invention provides an oxazole derivative having the following formula (II) or a salt thereof: 
[wherein each of R11 and R12 independently is an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and 1-3 halogen atom substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atom and a 3-7 membered substituent, or a phenylalkyl group having C1-4 alkyl portion, phenyl group, naphthyl group, pyridyl group, thienyl group, furyl group, quinolyl group, benzofuranyl group or benzothienyl group which optionally contains a substituent of halogen, hydroxyl, nitro, amino, C1-8 alkyl, C1-8 alkyl having 1-3 halogen substituents, C1-8 alkoxy, C1-8 alkoxy having 1-3 halogen substituents, phenyl, benzyl, phenyloxy, benzoyl or pyridyl; each of X11 and X12 independently is a bond, S(O)q in which q is an integer of 0 to 2, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94OR16) in which R16 is H or C1-8 alkyl; C(xe2x95x90O)NH, NHC(xe2x95x90O), SO2NH, NHSO2, CH(OR17) in which R17 is H or C1-8 alkyl, CHxe2x95x90CH, or Cxe2x89xa1C; Y1 is an alkylene chain having 1-8 carbon atoms and optionally a C1-8 alkyl or C1-8 alkoxy substituent; Z1 is O or S; each of R13 and R14 independently is an alkyl group having 1-8 carbon atoms and optionally a halogen or C1-8 alkoxy substituent; provided that X12 is neither O nor S(O)q when X11 is a bond, while X12 is not a bond when X11 is C(xe2x95x90O)NH].
Furthermore, the invention provides a thiazole derivative having the following formula (III) or a salt thereof: 
[wherein each of R21 and R22 independently is an alkyl group having 1-8 carbon atoms, an alkyl group having 1-8 carbon atoms and 1-3 halogen atom substituents, an alkenyl group having 2-8 carbon atoms, an alkynyl group having 2-8 carbon atoms, a 3-7 membered cycloalkyl group, an alkyl group having 1-8 carbon atom and a 3-7 membered substituent, or a phenylalkyl group having C1-4 alkyl portion, phenyl group, naphthyl group, pyridyl group, thienyl group, furyl group, quinolyl group, benzofuranyl group or benzothienyl group which optionally contains a substituent of halogen, hydroxyl, nitro, amino, C1-8 alkyl, C1-8 alkyl having 1-3 halogen substituents, C1-8 alkoxy, C1-8 alkoxy having 1-3 halogen substituents, phenyl, benzyl, phenyloxy, benzoyl or pyridyl; each of X21 and X22 independently is a bond, S(O)r in which r is an integer of 0 to 2, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94OR26) in which R26 is H or C1-8 alkyl; C(xe2x95x90O)NH, NHC(xe2x95x90O), SO2NH, NHSO2, CH(OR27) in which R27 is H or C1-8 alkyl, CHxe2x95x90CH, or Cxe2x89xa1C; Y2 is an alkylene chain having 1-8 carbon atoms and optionally a C1-8 alkyl or C1-8 alkoxy substituent; Z2 is O or S; each of R23 and R24 independently is an alkyl group having 1-8 carbon atoms and optionally a halogen or C1-8 alkoxy substituent; provided that X22 is neither O nor S(O)r when X21 is a bond, while X22 is not a bond when X21 is C(xe2x95x90O)NH].
Furthermore, the invention provides an activator of peroxisome proliferator activated receptor xcex4 which contains as an effective component a compound of the formula (I), an oxazole derivative of the formula (II), or a thiazole derivative of the formula (III) or their salts.
The present invention is described below in more detail.
The meanings of the symbols in the formula (I) are described below.
In the formula (I), examples of the alkyl groups having 1-8 carbon atoms for R1, R2, R5, R6, R7 and R8 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl.
Examples of the alkyl groups having 1-8 carbon atoms and a halogen substituent for R1 and R2 include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3 halogens such as fluorine, chlorine, and bromine. Preferred are trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl.
Examples of the alkenyl groups having 2-8 carbon atoms for R1 and R2 include vinyl and allyl.
Examples of the alkynyl groups having 2-8 carbon atoms for R1 and R2 include propargyl.
Examples of the 3-7 membered cycloalkyl group for R1 and R2 include cyclohexyl and cyclopentyl.
Examples of the alkyl groups having 1-8 carbon atoms and a 3-7 membered cycloalkyl substituent for R1 and R2 include cyclohexylmethyl and cyclopentylmethyl.
Examples of the arylalkyl groups (having C6-10 aryl portion and C1-4 alkyl portion) which optionally contain a substituent for R1 and R2 include alkyl groups having 1-4 carbon atoms substituted with a phenyl or naphthyl group which can have a substituent selected from the group consisting of halogens (e.g., fluorine, chlorine, bromine), hydroxyl, nitro, amino, C1-8 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl), C1-8 alkyl groups substituted with 1-3 halogen atoms (e.g., trifluoromethyl, trifluoroethyl), C1-8 alkoxy groups (e.g., methoxy, ethoxy), C1-8 alkyl groups substituted with 1-3 halogen atoms (e.g., 2-chloroethoxy), phenyl, benzyl, phenyloxy, benzoyl, and pyridyl. Preferred are methyl or ethyl group substituted with phenyl which can have a substituent of C1-6 alkyl (e.g., methyl, ethyl, propyl), C1-6 alkoxy (methoxy, ethoxy), or halogen (fluorine, chlorine, bromine). More preferred are benzyl, benzhydryl, and phenethyl.
Examples of the aryl groups optionally having a substituent for R1 and R2 include a phenyl or naphthyl group which can have a substituent selected from the group consisting of halogens (fluorine, chlorine, bromine), hydroxyl, nitro, amino, substituted amino (dimethylamino), C1-8 alkyl groups (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl), C1-8 alkyl groups substituted with 1-3 halogen atoms (trifluoromethyl, trifluoroethyl), C1-8 alkoxy groups (methoxy, ethoxy), C1-8 alkyl groups substituted with 1-3 halogen atoms (e.g., 2-chloroethoxy), acyl (acetyl, benzoyl), carboxyl, phenyl, benzyl, phenyloxy or pyridyl. Preferred are phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-fluorophenyl, 2-trifluoromethylphenyl, 4-chloro-2-hydroxyphenyl, 2-methylphenyl, 4-butylphenyl and naphthyl.
Examples of the heterocyclic groups optionally having a substituent for R1 and R2 include 5-8 membered heterocyclic groups having 1-3 ring-forming hetero atoms selected from the group of nitrogen atom, oxygen atom and sulfur atom and remaining carbon atoms, such as pyridyl, thienyl furyl, and thiazolyl, and further include condensed ring groups formed of these heterocyclic ring and benzene ring, such as quinolyl, benzofuranyl and benzothienyl. These heterocyclic groups can have a substituent such as that described for the aryl group having a substituent for R1 and R2.
Y is an alkylene chain which has 1-8 carbon atoms and may be substituted with C1-8 alkyl (e.g., methyl, ethyl, propyl) or C1-8 alkoxy (methoxy, ethoxy). Preferred are alkylene chains having 1-6 carbon atoms. More preferred are methylene, ethylene, and propylene.
Examples of the alkyl groups having 1-8 carbon atoms and optionally containing a substituent for R3 and R4 include alkyl groups having 1-8 carbon atoms which may have a halogen atom (e.g., fluorine, chlorine, bromine) or C1-8 alkoxy (e.g., methoxy, ethoxy). Preferred are methyl, ethyl, and propyl.
The meanings of the symbols in the formula (II) are described below.
In the formula (II), examples of the alkyl groups having 1-8 carbon atoms for R11, R12, R15, R16 and R17 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl.
Examples of the alkyl groups having 1-8 carbon atoms and a halogen substituent for R1 and R2 include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl which are substituted with 1-3 halogens such as fluorine, chlorine, and bromine. Preferred are trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl and 2-fluoroethyl.
Examples of the alkenyl groups having 2-8 carbon atoms for R11 and R12 include vinyl and allyl.
Examples of the alkynyl groups having 2-8 carbon atoms for R11 and R12 include propargyl.
Examples of the 3-7 membered cycloalkyl group for R11 and R12 include cyclohexyl and cyclopentyl.
Examples of the alkyl groups having 1-8 carbon atoms and a 3-7 membered cycloalkyl substituent for R11 and R12 include cyclohexylmethyl and cyclopentylmethyl.
Examples of the phenylalkyl (having C1-4 alkyl portion), phenyl, naphthyl, pyridyl, thienyl, furyl, quinolyl, benzofuranyl and benzothienyl groups for R11 and R12 may contain a substituent of halogen (e.g., fluorine, chlorine, bromine), hydroxyl, nitro, amino, C1-8 alkyl (e.g., methyl, ethyl, propyl), C1-8 alkyl substituted with 1-3 halogen atoms (e.g., trifluoromethyl, trifluoroethyl), C1-8 alkoxy (e.g., methoxy, ethoxy), C1-8 alkoxy substituted with 1-3 halogen atoms (e.g., chloroethoxy), phenyl, benzyl, phenyloxy, benzoyl, or pyridyl. The phenylalkyl group (having 1-4 carbon atoms) can be benzyl, benzhydryl and phenethyl.
Y1 is an alkylene chain which has 1-8 carbon atoms and may be substituted with C1-8 alkyl (e.g., methyl, ethyl, propyl) or C1-8 alkoxy (methoxy, ethoxy). Preferred are alkylene chains having 1-6 carbon atoms. More preferred are methylene, ethylene, and propylene.
Examples of the alkyl groups having 1-8 carbon atoms and optionally containing a substituent for R13 and R14 include alkyl groups having 1-8 carbon atoms which may have a halogen atom (e.g., fluorine, chlorine, bromine) or C1-8 alkoxy (e.g., methoxy, ethoxy). Preferred are methyl, ethyl, and propyl.
The meanings of the symbols in the formula (III) are described below.
R21, R22, R25, R26, R27 and Y2 of the formula (III) are those described for R11, R12, R15, R16, R17 and Y1 of the formula (II).
(1) A preferred compound of the invention is an oxazole derivative of the formula (II) in which X11 is a bond, and its salt.
(2) Another preferred compound of the invention is an oxazole derivative of the formula (II) or of (1) above in which X12 is a bond, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94OH), C(xe2x95x90O)NH, NHC(xe2x95x90O), CH(OH) or CHxe2x95x90CH, and its salt.
(3) A further preferred compound of the invention is an oxazole derivative of the formula (II) or of (1) or (2) in which R11 is a phenyl group, naphthyl group, pyridyl group, thienyl group, furyl group, quinolyl group, benzofuranyl group or benzothienyl group which optionally contains a substituent of halogen, hydroxyl, nitro, amino, C1-8 alkyl, C1-8 alkyl having 1-3 halogen substituents, C1-8 alkoxy, C1-8 alkoxy having 1-3 halogen substituents, phenyl, benzyl, phenyloxy, benzoyl or pyridyl, and its salt.
(4) A still further preferred compound of the invention is an oxazole derivative of the formula (II) or of (1) or (2) in which R11 is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-fluorophenyl, 2-trifluoromethylphenyl, 4-chloro-2-hydroxyphenyl, 2-methylphenyl, 4-butylphenyl or naphthyl, and its salt.
(5) A still further preferred compound of the invention is an oxazole derivative of the formula (II) or of (1)-(4) above in which R12 is an alkyl group having 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and 1-3 halogen atom substituents, and its salt.
(6) A still further preferred compound of the invention is an oxazole derivative of the formula (II) or of (1)-(5) above in which R12 is attached to the 2-position of the oxazole ring, and its salt.
(7) A still further preferred compound of the invention is a thiazole derivative of the formula (III) in which X21 is a bond, and its salt.
(8) A still further preferred compound of the invention is a thiazole derivative of the formula (III) or of (7) above in which X22 is a bond, C(xe2x95x90O), C(xe2x95x90Nxe2x80x94OH), C(xe2x95x90O)NH, NHC(xe2x95x90O), CH(OH) or CHxe2x95x90CH, and its salt.
(9) A still further preferred compound of the invention is a thiazole derivative of the formula (III) or of (7) or (8) in which R21 is a phenyl group, naphthyl group, pyridyl group, thienyl group, furyl group, quinolyl group, benzofuranyl group or benzothienyl group which optionally contains a substituent of halogen, hydroxyl, nitro, amino, C1-8 alkyl, C1-8 alkyl having 1-3 halogen substituents, C1-8 alkoxy, C1-8 alkoxy having 1-3 halogen substituents, phenyl, benzyl, phenyloxy, benzoyl or pyridyl, and its salt.
(10) A still further preferred compound of the invention is a thiazole derivative of the formula (III) or of (7) or (8) in which R21 is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-fluorophenyl, 2-trifluoromethylphenyl, 4-chloro-2-hydroxyphenyl, 2-methylphenyl, 4-butylphenyl or naphthyl, and its salt.
(11) A still further preferred compound of the invention is a thiazole derivative of the formula (III) or of (7)-(10) above in which R22 is an alkyl group having 1-8 carbon atoms, or an alkyl group having 1-8 carbon atoms and 1-3 halogen atom substituents, and its salt.
(12) A still further preferred compound of the invention is a thiazole derivative of the formula (III) or of (7)-(10) above in which R22 is attached to the 2-position of the oxazole ring, and its salt.
The compounds of the invention having the formula (I) can be present in the form of geometrical isomers such as cis and trans and optical isomers. These isomers are included in the compounds of the invention.
Further, the compounds of the invention can be in the form of pharmaceutically acceptable salts such as alkali metal salts, e.g., sodium salt and potassium salt.
The processes for preparing the compound of the formula (I) according to the invention are described below.
[Synthetic Process 1]
[in the formulas, Q is a releasing group such as tosyloxy or halogen (e.g., bromine), and R1, R2, R3, R4, R8, A, X1, X2, Y and Z are those described hereinbefore.
In the above-described process, the compound of the formula (I) according to the invention can be prepared by reacting a phenol or thiophenol compound of the general formula (a) with an acetic acid derivative of the general formula (b). The reaction can be carried out in a solvent such as methyl ethyl ketone in the presence of a base such as potassium carbonate.
The starting compound, i.e., the phenol or thiophenol compound of the formula (a), can be prepared by a process similar to the below-mentioned synthetic scheme:
[Synthesis Example 1 for Starting Compound]
[in the formulas, Bn is benzyl, and R1, R2 and A are those described hereinbefore.]
Further, the following synthetic schemes 2 and 3 can be utilized:
[Synthesis Example 2 for Starting Compound]
[Synthesis Example 3 for Starting Compound]
[in the formulas, Bn is benzyl, halo is halogen, n is an integer, W is a protective group for benzyl, and R1 and R2 are those described hereinbefore.]
In the above-illustrated synthesis example 2 for starting compound, the ethyl 2-benzoylacetate derivative is condensed with a halogen derivative, and the resulting ketone compound is decarbonized and then subjected to removal of the protecting group from benzyl, to give a phenol compound having an acyl substituent. The acylsubstituted phenol compound can be converted into a (1-hydroxyalkyl)phenol compound by means of a reducing agent such as NaBH4 or LiAlN4. Then, the (1-hydroxyalkyl)phenol compound can be converted into an olefin-substituted phenol compound by means of a halogenating reagent, a sulfonating reagent or a dehydrating reagent under acidic conditions using sulfuric acid. The olefin-substituted phenol compound can be obtained by a reaction between benzaldehyde and Wittig reagent. The olefin-substituted phenol compound can be converted into an alkyl-substituted phenol compound by catalytic reduction in a solvent such as ethanol in the presence of a catalyst such as Pdxe2x80x94C.
Further, the acyl-substituted phenol compound can be converted into an oxime compound utilizing the process illustrated in the synthesis example 3 for starting compound. Furthermore, a carbamoyl-substituted phenol compound can be obtained by the reaction with an amine and a benzoic chloride derivative (if required, a protective group is removed). An acylamino-substituted phenol compound is also obtained by the reaction with an acyl chloride and aniline (if required, a protective group is removed).
[Synthetic Process 2]
[in the formulas, R is C1-6 alkyl such as methyl or ethyl, and R11, R2, R3, R4, A, X1, X2, Y and Z are those described hereinbefore].
In the above-illustrated process for preparation, a compound of the formula (I) (R8=H) according to the invention can be obtained by the ester compound of the formula (c) is hydrolyzed in a solvent such as aqueous ethanol in the presence of a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
[Synthetic Process 3]
[in the formulas, Y0 is a C1-6 alkylene chain or a bond, and R1, R2, R3, R4, A, X1 and Z are those described hereinbefore].
In the above-illustrated process, a compound of the formula (I) (X2=bond) according to the invention can be obtained by subjecting the olefin compound of the formula (e) to a reduction reaction in ethanol in the presence of a catalyst such as Ptxe2x80x94C.
[Synthetic Process 4]
[in the formulas, R1, R2, R3, R4, R8, A, X1, Y and Z are those described hereinbefore].
In the above-illustrated process, a compound of the formula (I) (X2xe2x95x90C(xe2x95x90Nxe2x80x94OH)) according to the invention can be obtained by reacting the ketone compound of the formula (g) with hydroxylamine.
The representative compounds of the invention are described below.
(1-1) Compounds of the Following Formula (I-a)
Compounds of the formula (I) in which A is O, Z is O, R8 is H, and X1 is attached to the 4-position of the oxazole ring.
(1-2) Compounds of the Above-illustrated Formula (I-a)
(2) Compounds of the Following Formula (I-b)
Compounds of the formula (I) in which A is O, Z is S, R8 is H, and X1 is attached to the 4-position of the oxazole ring.
(3-1) Compounds of the Following Formula (I-c)
Compounds of the formula (I) in which A is not O, each of R3 and R4 is methyl, Z is O, R8 is H, and X1 is attached, for example, to the 4-position of the thiazole ring.
(3-2) Compounds of the Above-illustrated Formula (I-c)
(4-1) Compounds of the Following Formula (I-d)
Compounds of the formula (I) in which each of R3 and R4 is methyl, Z is O, R8 is H, and X1 is attached, for example, to the 2-position of the thiazole ring.
(4-2) Compounds of the Above-illustrated Formula (I-d)
(5-1) Compounds of the Following Formula (I-e)
Compounds of the formula (I) in which each of R3 and R4 is methyl, Z is O, R8 is H, and X1 is attached, for example, to the 5-position of the thiazole ring.
(5-2) Compounds of the Above-illustrated Formula (I-e)
(6) Oxazole Derivatives of the Following Formula: 
[in the formula, R1, R2, R4, R5, X1, X2 and Y1 are those described in Tables 10 to 15].
(7) Oxazole Derivatives of the Following Formula: 
[in the formula, R1, R2, R4, R5, X1, X2 and Y1 are those described in Tables 16 to 21].
(8) Thiazole Derivatives of the Following Formula:
The compounds of the aforementioned general formula (I) in which A is S, and Z is S. 
(9) Thiazole Derivatives of the Following Formula:
The compounds of the aforementioned general formula (I) in which A is S, and Z is O. 
[in the formula, R1, R2, R4, R5, X1, X2 and Y1 are those described in Tables 23 and 24].
The pharmacological effects of the invention are described below.
The PPARxcex4 activating effect of the compound of the invention was determined by the following method:
A chimeric receptor expression plasmid (GAL4-hPPARxcex4 LBD), a reporter plasmid (UASx4-TK-LUC) and xcex2-galactosidase (xcex2-GAL) are transfected into CV-1 cells by utilizing a lipofection reagent DMRIE-C (Life Technologies). Subsequently, it is incubated for 40 hours in the presence of a compound of the invention or a compound for comparison (L-165041), and then the luciferase activity and xcex2-GAL activity are measured on the soluble cells.
The luciferase activity is calibrated by the xcex2-GAL activity, and a relative ligand activity is calculated under the condition that the luciferase activity of the cells treated by L-165041 is set to 100%). In the same manner, relative ligand activities to PPARxcex4 and xcex3 transactivation activitis are calculated (see the below-mentioned Example 9).
As seen from Table 25, the compounds of the invention (Examples 1-6) show the same or higher PPARxcex4 activating effect, as compared with L-165041. The compounds of the invention given in Examples 1 and 5 show activity to PPARxcex4 selectively higher than activity to PPARxcex1 and xcex3.
Further, as seen from Table 26, the compounds of the invention (e.g., Example 7-6) show the same or higher PPARxcex4 activating effect, as compared with L-165041. Furthermore, the compounds of the invention given in Example 7-12, etc., show activity to PPARxcex4 selectively higher than activity to PPARxcex1 and xcex3.
Furthermore, as seen from Table 27, the compounds of the invention (e.g., Examples 8-1 to 8-4) show the same or higher PPARxcex4 activating effect, as compared with L-165041.
Apparently, the compounds of the invention having the general formula (I) show excellent PPARxcex4 activating effect. Accordingly, these compounds are expected to serve as remedy for prevention and treatment of the following diseases: hyperglycemia, hyperlipidemia, obesity, syndrome X, hyperchloresterolemia, hyperlipopreoteinemia, other dysbolismic diseases, hiperlipemia, arterial sclerosis, diseases of cardiovascular systems, hyperphagia, ischemic diseases, malignant tumors such as lung cancer, mammary cancer, colonic cancer, cancer of great intestine, and ovary cancer, Alzheimer""s disease, inflammatory disease, osteoporosis (Mano H. et al., (2000) J. Biol. Chem., 175:8126-8132), Basedow""s disease, and adrenal cortical dystrophy.
The compound of the invention can be administered to human beings by ordinary administration methods such as oral administration or parenteral administration.
The compound can be granulated in ordinary manners for the preparation of pharmaceuticals. For instance, the compound can be processed to give pellets, granule, powder, capsule, suspension, injection, suppository, and the like.
For the preparation of these pharmaceuticals, ordinary additives such as vehicles, disintegrators, binders, lubricants, dyes, and diluents. As the vehicles, lactose, D-mannitol, crystalline cellulose and glucose can be mentioned. Further, there can be mentioned starch and carboxymethylcellulose calcium (CMC-Ca) as the disintegrators, magnesium stearate and talc as the lubricants, and hydroxypropylcellulose (HPC), gelatin and polyvinylpirrolidone (PVP) as the binders.
The compound of the invention can be administered to an adult generally in an amount of 0.1 mg to 100 mg a day by parenteral administration and 1 mg to 2,000 mg a day by oral administration. The dosage can be adjusted in consideration of age and conditions of the patient.
The invention is further described by the following non-limiting examples.